Variant 2-219013929-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_194302.4(CFAP65):c.3718A>G(p.Ile1240Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1240F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CFAP65
NM_194302.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.771

Variant links:

Genes affected

CFAP65 (HGNC:25325): (cilia and flagella associated protein 65) The protein encoded by this gene has putative coiled-coil domains and may be a transmembrane protein. The chicken ortholog of this gene is involved in the Rose-comb mutation, which is a large chromosome inversion, resulting in altered comb morphology and defects in sperm motility. [provided by RefSeq, Aug 2016]

CFAP65 links:

ENSG00000224090 (HGNC:):

ENSG00000224090 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049974322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP65	NM_194302.4 linkuse as main transcript	c.3718A>G	p.Ile1240Val	missense_variant	22/35	ENST00000341552.10	NP_919278.2	Q6ZU64-1B4DZ05

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CFAP65	ENST00000341552.10 linkuse as main transcript	c.3718A>G	p.Ile1240Val	missense_variant	22/35	5	NM_194302.4	ENSP00000340776.5	Q6ZU64-1
CFAP65	ENST00000453220.5 linkuse as main transcript	c.3718A>G	p.Ile1240Val	missense_variant	20/33	5		ENSP00000409117.1	Q6ZU64-1
ENSG00000224090	ENST00000441450.1 linkuse as main transcript	n.200T>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250590

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461700

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.3718A>G (p.I1240V) alteration is located in exon 22 (coding exon 20) of the CFAP65 gene. This alteration results from a A to G substitution at nucleotide position 3718, causing the isoleucine (I) at amino acid position 1240 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.76

CADD

Benign

9.5

DANN

Benign

0.55

DEOGEN2

Benign

0.025

T;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.58

.;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.050

T;T

MetaSVM

Benign

-0.93

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.080

N;N

REVEL

Benign

0.013

Sift

Benign

0.58

T;T

Sift4G

Benign

0.67

T;T

Polyphen

0.0040

B;B

Vest4

0.043

MutPred

0.43

Gain of catalytic residue at I1240 (P = 0.0189);Gain of catalytic residue at I1240 (P = 0.0189);

MVP

0.14

MPC

0.064

ClinPred

0.019

GERP RS

1.1

Varity_R

0.024

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over